Substantially pure O-desmethylvenlafaxine and processes for preparing it

ABSTRACT

Methods for preparing substantially pure O-desmethylvenlafaxine are described.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of the following U.S.Provisional Patent Application Nos. 60/792,801, filed Apr. 17, 2006;60/796,739, filed May 1, 2006; 60/899,166, filed Feb. 1, 2007;60/902,418, filed Feb. 20, 2007; 60/872,955, filed Dec. 4, 2006; and60/903,988, filed Feb. 27, 2007. The contents of these applications areincorporated herein by reference.

FIELD OF THE INVENTION

The invention encompasses substantially pure O-desmethylvenlafaxine.

BACKGROUND OF THE INVENTION

Venlafaxine,(±)-1-[2-(Dimethylamino)-1-(4-ethyoxyphenyl)ethyl]cyclo-hexanol is thefirst of a class of anti-depressants. Venlafaxine acts by inhibitingre-uptake of norepinephrine and serotonin, and is an alternative to thetricyclic anti-depressants and selective re-uptake inhibitors.Venlafaxine has the following chemical formula, Formula I:

O-desmethylvenlafaxine,4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol, is a majormetabolite of venlafaxine and has been shown to inhibit norepinephrineand serotonin uptake. See Klamerus, K. J. et al., “Introduction of theComposite Parameter to the Pharmacokinetics of Venlafaxine and itsActive O-Desmethyl Metabolite,” J. Clin. Pharmacol. 32:716-724 (1992).O-desmethylvenlafaxine has the following chemical formula, Formula II:

Processes for the synthesis of O-desmethylvenlafaxine, comprising a stepof demethylation of the phenol group of venlafaxine, are described inU.S. Pat. Nos. 7,026,508 and 6,689,912, and in U.S. publication No.2005/0197392, which are incorporated herein by reference.

The synthesis disclosed in the above references is performed accordingto the following scheme:

“MBC” refers to methyl benzyl cyanide, “CMBC” refers to cyclohexylmethylbenzyl cyanide, “DDMV” refers to didesmethyl venlafaxine, and“ODV” refers to O-desmethylvenlafaxine.

Like any synthetic compound, O-desmethylvenlafaxine can containextraneous compounds or impurities that can come from many sources. Theycan be unreacted starting materials, by-products of the reaction,products of side reactions, or degradation products. Impurities inO-desmethylvenlafaxine or any active pharmaceutical ingredient (API) areundesirable and, in extreme cases, might even be harmful to a patientbeing treated with a dosage form containing the API.

It is also known in the art that impurities in an API may arise fromdegradation of the API itself, which is related to the stability of thepure API during storage, and the manufacturing process, including thechemical synthesis. Process impurities include unreacted startingmaterials, chemical derivatives of impurities contained in startingmaterials, synthetic by-products, and degradation products.

In addition to stability, which is a factor in the shelf life of theAPI, the purity of the API produced in the commercial manufacturingprocess is clearly a necessary condition for commercialization.Impurities introduced during commercial manufacturing processes must belimited to very small amounts, and are preferably substantially absent.For example, the ICH Q7A guidance for API manufacturers requires thatprocess impurities be maintained below set limits by specifying thequality of raw materials, controlling process parameters, such astemperature, pressure, time, and stoichiometric ratios, and includingpurification steps, such as crystallization, distillation, andliquid-liquid extraction, in the manufacturing process.

The product mixture of a chemical reaction is rarely a single compoundwith sufficient purity to comply with pharmaceutical standards. Sideproducts and by-products of the reaction and adjunct reagents used inthe reaction will, in most cases, also be present in the productmixture. At certain stages during processing of an API, such asO-desmethylvenlafaxine, it must be analyzed for purity, typically, byHPLC, NMR or TLC analysis, to determine if it is suitable for continuedprocessing and, ultimately, for use in a pharmaceutical product. The APIneed not be absolutely pure, as absolute purity is a theoretical idealthat is typically unattainable. Rather, purity standards are set withthe intention of ensuring that an API is as free of impurities aspossible, and, thus, is as safe as possible for clinical use. Asdiscussed above, in the United States, the Food and Drug Administrationguidelines recommend that the amounts of some impurities be limited toless than 0.1 percent.

Generally, side products, by-products, and adjunct reagents(collectively “impurities”) are identified spectroscopically and/or withanother physical method, and then associated with a peak position, suchas that in a chromatogram, or a spot on a TLC plate. (Strobel p. 953,Strobel, H. A.; Heineman, W.R., Chemical Instrumentation: A SystematicApproach, 3rd dd. (Wiley & Sons: New York 1989)). Thereafter, theimpurity can be identified, e.g., by its relative position in thechromatogram, where the position in a chromatogram is conventionallymeasured in minutes between injection of the sample on the column andelution of the particular component through the detector. The relativeposition in the chromatogram is known as the “retention time.”

Thus, because of its medical uses, it is desirable to obtainsubstantially pure O-desmethylvenlafaxine.

SUMMARY OF THE INVENTION

In one embodiment the present invention provides substantially pureO-desmethylvenlafaxine containing less than about 5% area by HPLC, morepreferably less than about 3% area by HPLC, even more preferably lessthan about 1% area by HPLC of total impurities.

Preferably, the O-desmethylvenlafaxine contains less than about 0.7%area by HPLC of total impurities. More preferably, less than about 0.2%area by HPLC of total impurities and most preferably, theO-desmethylvenlafaxine contains less than about 0.07% area by HPLC oftotal impurities.

In another embodiment, the present invention provides a process forpreparing substantially pure O-desmethylvenlafaxine comprising:combining under reduced pressure venlafaxine, an organic solvent and areagent selected from the group consisting of: thiophenol, sodiumsulfide and C₁-C₈ alkyl thiolate, to form a mixture, heating the mixtureto a temperature of about 30° C. to about 220° C., and recoveringO-desmethylvenlafaxine.

In another embodiment, the present invention provides a process forpreparing substantially pure O-desmethylvenlafaxine comprising:combining venlafaxine, an organic solvent and C₁-C₈ alkyl thiolate orsodium sulfide to form a mixture, heating the mixture to a temperatureof about 100° C. to about 210° C., and recoveringO-desmethylvenlafaxine.

In another embodiment, the present invention provides a process forpreparing substantially pure O-desmethylvenlafaxine comprising:combining venlafaxine and thiophenol to form a mixture, heating themixture to a temperature of about 100° C. to about 210° C., andrecovering O-desmethylvenlafaxine.

In yet another embodiment, the present invention provides the use ofC₁-C₈ alkyl thiolate and sodium sulfide for the demethylation ofvenlafaxine.

In yet another embodiment, the present invention provides a process forpreparing substantially pure O-desmethylvenlafaxine comprising:preparing tridesmethyl venlafaxine as described in the co-pendingapplication 60/849,216 (which is incorporated herein by reference);converting said tridesmethyl venlafaxine to O-desmethylvenlafaxine; andrecovering O-desmethylvenlafaxine.

In a further embodiment, the invention is directed to an analyticalmethod for testing the chemical purity of O-desmethylvenlafaxine.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising substantially pure O-desmethylvenlafaxine and apharmaceutically acceptable excipient.

In yet another embodiment, the present invention provides a process forpreparing a pharmaceutical formulation comprising mixing substantiallypure O-desmethylvenlafaxine and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “substantially pure” refers toO-desmethylvenlafaxine having a purity, measured as % area HPLC, ofabout 95% or more. Preferably, substantially pure O-desmethylvenlafaxinehas a purity of about 97% area by HPLC, more preferably of about 99%area by HPLC, even more preferably of about 99.3% area by HPLC, mostpreferably of about 99.8% area by HPLC.

The present invention provides O-desmethylvenlafaxine (ODV) containingless than about 5% area by HPLC, preferably less than about 3% area byHPLC, more preferably less than 1% area by HPLC, of total impurities.The term “% area by HPLC” as used herein refers to the area in an HPLCchromatogram of one or more peaks compared to the total area of allpeaks in the HPLC chromatogram expressed in percent of the total area.Further the purity of O-desmethyl venlafaxine may be expressed herein as“HPLC” purity. As such, “HPLC purity”, is a calculation of the areaunder the O-desmethyl venlafaxine peak divided by the total area underthe curve in an HPLC chromatogram.

Preferably, the O-desmethylvenlafaxine contains less than about 0.7%area by HPLC of total impurities. More preferably, less than about 0.2%area by HPLC of total impurities and most preferably, theO-desmethylvenlafaxine contains less than about 0.07% area by HPLC oftotal impurities.

The O-desmethylvenlafaxine provided by the present invention is obtainedeither as a racemate or as optically pure O-desmethylvenlafaxine.

It would be apparent to any skilled artisan that further crystallizingcrude O-desmethylvenlafaxine could afford higher purity.

In another embodiment, the present invention provides a process forpreparing substantially pure O-desmethylvenlafaxine comprising:combining, preferably under reduced pressure, venlafaxine (VNL), anorganic solvent and a reagent selected from the group consisting of:thiophenol, sodium sulfide and a C₁-C₈ alkyl thiolate, to form amixture, preferably heating the mixture to a temperature of from about30° C. to about 220° C., preferably from about 30° C. to about 100° C.,and recovering substantially pure O-desmethylvenlafaxine.

As used herein, the term “reduced pressure” refers to a pressure belowabout 1 atmosphere, preferably to a pressure of less than 0.5atmosphere, more preferably to a pressure of less than about 0.1atmosphere.

The organic solvent can be selected from the group consisting of: C₃-C₇ketones, C₃-C₇ esters, C₅-C₈ aliphatic hydrocarbons or C₆-C₁₂ aromatichydrocarbons, high boiling point solvents, C₂-C₈ ethers, chlorinatedhydrocarbons, and C₂-C₈ alcohols. More preferably, the solvent isselected from the group consisting of: acetone, ethyl acetate, toluene,DMF, NMP, DMA, THF and ethanol.

As used herein, the term “high boiling point solvent” refers to asolvent having a boiling point higher than about 100° C. Preferably, thehigh boiling point solvent is selected from the group consisting of:toluene, dimethylformamide (DMF), dimethylsulfoxide (DMSO),N-methyl-2-pyridone, N-methyl-2-pyrrolidone, 1-methyl-2-pyrrolidinone(NMP) and dimethylacetamide (DMA). More preferably, the high boilingpoint solvent is DMA, DMF or NMP.

Whenever NMP is used, the ratio of NMP to venlafaxine is preferably 1 to20 (by volume), more preferably, 2 to 4 (by volume).

Whenever DMA or DMF are used, the ratio of DMA and DMF to venlafaxine ispreferably at least about 1 volume, more preferably, 1 to 10 (byvolume), most preferably, about 2.5 volumes.

Whenever thiophenol is used in the process, a catalyst is preferablyemployed in the reaction mixture. More preferably, the catalyst is abase. Most preferably, the catalyst is an alkali metal base, such aspotassium carbonate.

Preferably, the substantially pure O-desmethylvenlafaxine obtained bythe process above contains less than about 0.7% area by HPLC of totalimpurities. More preferably, less than about 0.2% area by HPLC of totalimpurities and most preferably, the substantially pureO-desmethylvenlafaxine obtained by the process above contains less thanabout 0.07% area by HPLC of total impurities.

The O-desmethylvenlafaxine may be recovered from the mixture by anymethod known to the skilled artisan.

Preferably, the O-desmethylvenlafaxine thus obtained is in a crystallineform, characterized by X-ray powder diffraction reflections at about:12.1, 13.2, 15.9 and 20.4 degrees two theta ±0.2 degrees two theta.

In another embodiment, the present invention provides a process forpreparing substantially pure O-desmethylvenlafaxine comprising:combining venlafaxine, an organic solvent and a C₁-C₈ alkyl thiolate orsodium sulfide to form a mixture, heating the mixture to a temperatureof about 100° C. to about 210° C., preferably of about 100° C. to about190° C., more preferably of about 135° C. to about 190° C., andrecovering substantially pure O-desmethylvenlafaxine.

The organic solvent used is as described above.

Whenever NMP is used, the ratio of NMP to venlafaxine is preferably 1 to20 (by volume), more preferably, 2 to 4 (by volume).

Whenever DMA or DMF are used, the ratio of DMA and DMF to venlafaxine ispreferably at least about 1 volume, more preferably, 1 to 10 (byvolume), most preferably, about 2.5 volumes.

Preferably, the substantially pure O-desmethylvenlafaxine obtained bythe process above contains less than about 0.7% area by HPLC of totalimpurities. More preferably, less than about 0.2% area by HPLC of totalimpurities and most preferably, the O-desmethylvenlafaxine obtained bythe process above contains less than about 0.07% area by HPLC of totalimpurities.

The O-desmethylvenlafaxine may be recovered from the mixture by anymethod known to the skilled artisan.

Preferably, the O-desmethylvenlafaxine thus obtained is in a crystallineform, characterized by X-ray powder diffraction reflections at about:12.1, 13.2, 15.9 and 20.4 degrees two theta ±0.2 degrees two theta.

In another embodiment, the present invention provides a process forpreparing substantially pure O-desmethylvenlafaxine comprising:combining venlafaxine and thiophenol to form a mixture, heating themixture to a temperature of about 100° C. to about 210° C., preferablyof about 100° C. to about 190° C., more preferably of about 135° C. toabout 190° C., and recovering substantially pure O-desmethylvenlafaxine.

Optionally, the process above can be performed in the presence of anon-hydroxilic or nonethereal solvent. The solvent can be selected fromthe group consisting of: NMP, DMSO, DMF, DMA, carbowax, marlotherm andsilicon oil. Preferably, the solvent is NMP.

Whenever NMP is used, the ratio of NMP to venlafaxine is preferably 1 to20 (by volume), more preferably, 2 to 4 (by volume).

A catalyst is preferably employed in the reaction mixture of venlafaxineand thiophenol. More preferably, the catalyst is a base. Mostpreferably, the catalyst is an alkali metal base, such as potassiumcarbonate.

Preferably, the substantially pure O-desmethylvenlafaxine obtained bythe process above, contains less than about 0.7% area by HPLC of totalimpurities. More preferably, less than about 0.2% area by HPLC of totalimpurities and most preferably, the O-desmethylvenlafaxine obtained bythe process above contains less than about 0.07% area by HPLC of totalimpurities.

The O-desmethylvenlafaxine may be recovered from the mixture by anymethod known to the skilled artisan.

Preferably, the O-desmethylvenlafaxine thus obtained is in a crystallineform, characterized by X-ray powder diffraction reflections at about:12.1, 13.2, 15.9 and 20.4 degrees two theta ±0.2 degrees two theta.

All processes for preparing substantially pure O-desmethylvenlafaxinedescribed above may be followed by slurrying the obtainedO-desmethylvenlafaxine in a mixture of an organic solvent and water, inorder to reduce salts impurities. The substantially pureO-desmethylvenlafaxine obtained by slurrying has assay purity of atleast about 95%, more preferably, an assay purity of 99%. Preferably,the organic solvent/water mixture can be an alcohol/water mixture orwater/acetonitrile mixture, more preferably the alcohol/water mixture isa C₁-C₄ alcohol/water mixture, most preferably the alcohol/water mixtureis an isopropanol/water mixture.

As used herein the term “assay purity” refers to a purity determined bya well known method which calculates the mass of O-desmethyl venlafaxineby comparing the area percent of the sample to the area percent of astandard.

Optionally, O-desmethylvenlafaxine is slurried in a water/IPA mixture.Preferably, the water/IPA mixture is in a ratio of 15:25 to 80:20 (byvolume), more preferably the ratio is 80:20 (by volume).

The slurry is may be maintained for about 5 minutes to about 5 hours,preferably for about 30 minutes to about 4 hours, more preferably forabout 1 hour to about 3 hours, most preferably for about 2 hours, at atemperature of about 20° C. to about 70° C., preferably at about 20° C.to about 40° C., more preferably at about room temperature, to obtainsubstantially pure O-desmethylvenlafaxine having an assay purity ofabout 95%, preferably of about 99%. The substantially pureO-desmethylvenlafaxine may be recovered from the slurry by any methodknown to the skilled artisan. Preferably, recovery comprisesprecipitation of O-desmethyl venlafaxine from an aqueous solution orsuspension in water/IPA wherein the pH is adjusted to 7.5-13.5,preferably to 7.5 to 10, more preferably to a pH of about 8. Adjustingthe pH comprises adding an acid, preferably the acid is selected fromHCl and an organic acid, more preferably the acid is citric acid orsuccinic acid, most preferably the acid is succinic acid.

In yet another embodiment, the present invention provides the use ofC₁-C₈ alkyl thiolate and sodium sulfide for the demethylation ofvenlafaxine.

In yet another embodiment, the present invention provides a process forpreparing substantially pure O-desmethylvenlafaxine comprising:preparing tridesmethyl venlafaxine (TDMV) as described in the co-pendingapplication 60/849,216, which is incorporated herein by reference;converting said tridesmethyl venlafaxine to O-desmethylvenlafaxine; andrecovering substantially pure O-desmethylvenlafaxine from the reactionmixture.

A process for preparing tridesmethyl venlafaxine comprises: combiningdidesmethylvenlafaxine, a high boiling point solvent, and a thiolate toform a mixture, heating the mixture to a temperature of about 100° C. toabout 220° C., preferably of about 140° C. to about 210° C., morepreferably to a temperature of about 155° C. to about 210° C., andoptionally recovering tridesmethyl venlafaxine from the mixture.

The tridesmethyl venlafaxine obtained by the process above preferablycontains less than 5% area by HPLC of total impurities.

Preferably, the high boiling point solvent is as described above.

Preferably, the thiolate is a high molecular weight thiolate or arenethiolate. More preferably, the thiolate is sodium dodecanethiolate orthiophenol. The sodium dodecanethiolate can be obtained by any methodknown to the skilled artisan, such as combining sodium methoxide,methanol and dodecanethiol.

Whenever thiophenol is used, a catalyst is preferably employed in thereaction mixture. More preferably, the catalyst is a base. Mostpreferably, the catalyst is an alkali metal base, such as potassiumcarbonate is the catalyst.

Preferably, the mixture is heated to a temperature of about 155° C. toabout 210° C.

The tridesmethyl venlafaxine may be recovered from the mixture by anymethod known to the skilled artisan.

The conversion of tridesmethyl venlafaxine to O-desmethylvenlafaxine canalso be performed as described in the co-pending application 60/849,216,which is incorporated herein by reference. This process comprises:combining a solution of tridesmethyl venlafaxine and a formaldehydesource with sodium borohydride or sodium triacetoxy borohydride toobtain a slurry and optionally recovering the O-desmethylvenlafaxinefrom the slurry.

Optionally, the tridesmethyl venlafaxine starting material is in asolution with an organic solvent such as a C₁₋₄ alcohol.

Optionally, the process is performed under acidic conditions.Preferably, the acidic source is an organic acid, such as formic acid oran acetic acid.

Preferably, prior to combining the sodium borohydride or sodiumtriacetoxy borohydride, the solution is cooled to a temperature of lessthan about 10° C., more preferably less than about 5° C.

Substantially pure O-desmethylvenlafaxine may be further recovered fromthe reaction mixture by any method known to the skilled artisan.Preferably, recovering substantially pure O-desmethylvenlafaxinecomprises adjusting the pH of a suspension containing crudeO-desmethylvenlafaxine, for example the reaction mixture from theconversion step, to a pH of about 7.5-13.5, obtaining substantially pureO-desmethylvenlafaxine. Adjusting the pH of the suspension containingcrude O-desmethylvenlafaxine may result or enable precipitation ofsubstantially pure O-desmethylvenlafaxine from the suspension. Thesuspension containing crude O-demethylvenlafaxine may be the suspensionfrom the reaction mixture of the conversion of tridesmethylvenlafaxineto O-desmethylvenlafaxine or a suspension in a water/C₁-C₄ alcoholmixture. The pH may be adjusted with any suitable organic or inorganicacid, preferably the pH is adjusted with citric acid or succinic acid.In recovering substantially pure O-desmethylvenlafaxine the pH ispreferably adjusted to pH of about 7.5-10, more preferably to pH ofabout 8. Recovering the substantially pure O-desmethylvenlafaxine mayfurther comprise filtering the obtained substantially pureO-desmethylvenlafaxine. Optionally, an anti-solvent is added to the pHadjusted suspension, wherein the anti-solvent is a water misciblesolvent. Preferably, the anti-solvent is a C1-C4 alcohol, morepreferably isopropanol (IPA).

Preferably, the substantially pure O-desmethylvenlafaxine obtained bythe process above, contains less than about 0.7% area by HPLC of totalimpurities. More preferably, less than about 0.2% area by HPLC of totalimpurities and most preferably, the O-desmethylvenlafaxine obtained bythe process above contains less than about 0.07% area by HPLC of totalimpurities.

The O-desmethylvenlafaxine may be recovered from the slurry by anymethod known to the skilled artisan.

In a further embodiment, the invention is directed to an analyticalmethod for testing the chemical purity of O-desmethylvenlafaxinecomprising combining an O-desmethylvenlafaxine sample with a mixture ofacetonitrile:buffer in a ratio of about 3:7, to obtain a solution;injecting the solution onto a C-18 column, for example a Zorbax SB C-184.6*250 mm Part No. 28105-020 or similar column, followed by eluting thesample from the column at about 55 min using a mixture of acetonitrile:buffer (about 3:7) (referred to as eluent A) and a mixture ofacetonitrile: buffer: trifluoroacetic acid: triethylamine (referred toas eluent B) as an eluent, and measuring the chemical purity of therelevant sample with a UV detector. Eluent B is preferably prepared byadding to a mixture of about 700 parts acetonitrile and about 300 partsbuffer, about 1.6 parts trifluoroacetic acid and about 2.9 partstriethylamine and adjusting the resulting mixture to about pH 3.0, morepreferably eluent B is prepared by combining about 700 ml acetonitrile,about 300 ml Buffer, about 1.6 ml trifluoroacetic acid, and 2.9 mltriethylamine and adjusting to a pH of about 3.0.

Preferably, the buffer contains about 0.4% trifluoroacetic acid, about0.7% triethylamine and about 98.9% water having a pH of about 3.0.

Preferably, the eluent used may be a mixture of eluent A and eluent B,wherein the ratio of them varies over the time, i.e. a gradient eluent.At the time 0 minutes, the eluent contains 100% of eluent A and 0% ofeluent B. At about 21 minutes, the eluent preferably contains about 100%of eluent A and about 0% of eluent B. At about 55 minutes, the eluentpreferably contains about 45% of eluent A and about 55% of eluent B.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising substantially pure O-desmethylvenlafaxine and apharmaceutically acceptable excipient.

In yet another embodiment, the present invention provides a process forpreparing a pharmaceutical formulation comprising mixing substantiallypure O-desmethylvenlafaxine and a pharmaceutically acceptable carrier.

Pharmaceutical compositions may be prepared as medicaments to beadministered orally, parenterally, rectally, transdermally, bucally, ornasally. Suitable forms for oral administration include tablets,compressed or coated pills, dragees, sachets, hard or gelatin capsules,sub-lingual tablets, syrups, and suspensions. Suitable forms ofparenteral administration include an aqueous or non-aqueous solution oremulsion, while for rectal administration, suitable forms foradministration include suppositories with hydrophilic or hydrophobicvehicle. For topical administration, the invention provides suitabletransdermal delivery systems known in the art, and for nasal delivery,there are provided suitable aerosol delivery systems known in the art.

In addition to the active ingredient(s), the pharmaceutical compositionsof the present invention may contain one or more excipients oradjuvants. Selection of excipients and the amounts to use may be readilydetermined by the formulation scientist based upon experience andconsideration of standard procedures and reference works in the field.

Diluents increase the bulk of a solid pharmaceutical composition and maymake a pharmaceutical dosage form containing the composition easier forthe patient and care giver to handle. Diluents for solid compositionsinclude, for example, microcrystalline cellulose (e.g. Avicel®),microfine cellulose, lactose, starch, pregelitinized starch, calciumcarbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasiccalcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol, and talc.

Solid pharmaceutical compositions that are compacted into a dosage form,such as a tablet, may include excipients whose functions include helpingto bind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions includeacacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulosesodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenatedvegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g.Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquidglucose, magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinizedstarch, sodium alginate, and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach may be increased by the addition of a disintegrantto the composition. Disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g. Explotab®), andstarch.

Glidants can be added to improve the flowability of a non-compactedsolid composition and to improve the accuracy of dosing. Excipients thatmay function as glidants include colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, talc, and tribasic calciumphosphate.

When a dosage form such as a tablet is made by the compaction of apowdered composition, the composition is subjected to pressure from apunch and die. Some excipients and active ingredients have a tendency toadhere to the surfaces of the punch and die, which can cause the productto have pitting and other surface irregularities. A lubricant can beadded to the composition to reduce adhesion and ease the release of theproduct from the die. Lubricants include magnesium stearate, calciumstearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenatedcastor oil, hydrogenated vegetable oil, mineral oil, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate,stearic acid, talc, and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that may be included in the composition ofthe present invention include maltol, vanillin, ethyl vanillin, menthol,citric acid, fumaric acid, ethyl maltol, and tartaric acid.

Solid and liquid compositions may also be died using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention, theactive ingredient and any other solid excipients are suspended in aliquid carrier such as water, vegetable oil, alcohol, polyethyleneglycol, propylene glycol or glycerin.

Liquid pharmaceutical compositions may contain emulsifying agents todisperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that may be useful in liquid compositions of the presentinvention include, for example, gelatin, egg yolk, casein, cholesterol,acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,cetostearyl alcohol, and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention may alsocontain a viscosity enhancing agent to improve the mouth-feel of theproduct and/or coat the lining of the gastrointestinal tract. Suchagents include acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanth,and xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol, and invert sugar may be added toimprove the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxy toluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improvestorage stability.

According to the present invention, a liquid composition may alsocontain a buffer such as gluconic acid, lactic acid, citric acid oracetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodiumacetate.

Selection of excipients and the amounts used may be readily determinedby the formulation scientist based upon experience and consideration ofstandard procedures and reference works in the field.

The solid compositions of the present invention include powders,granulates, aggregates, and compacted compositions. The dosages includedosages suitable for oral, buccal, rectal, parenteral (includingsubcutaneous, intramuscular, and intravenous), inhalant, and ophthalmicadministration. Although the most suitable administration in any givencase will depend on the nature and severity of the condition beingtreated, the most preferred route of the present invention is oral. Thedosages may be conveniently presented in unit dosage form and preparedby any of the methods well known in the pharmaceutical arts.

Dosage forms include solid dosage forms like tablets, powders, capsules,suppositories, sachets, troches, and lozenges, as well as liquid syrups,suspensions, and elixirs.

The dosage form of the present invention may be a capsule containing thecomposition, preferably a powdered or granulated solid composition ofthe invention, within either a hard or soft shell. The shell may be madefrom gelatin, and, optionally, contain a plasticizer such as glycerinand sorbitol, and an opacifying agent or colorant.

The active ingredient and excipients may be formulated into compositionsand dosage forms according to methods known in the art. A compositionfor tableting or capsule filling may be prepared by wet granulation. Inwet granulation, some or all of the active ingredients and excipients inpowder form are blended, and then further mixed in the presence of aliquid, typically water, that causes the powders to clump into granules.The granulate is screened and/or milled, dried, and then screened and/ormilled to the desired particle size. The granulate may then be tabletedor other excipients may be added prior to tableting, such as a glidantand/or a lubricant.

A tableting composition may be prepared conventionally by dry blending.For example, the blended composition of the actives and excipients maybe compacted into a slug or a sheet, and then comminuted into compactedgranules. The compacted granules may subsequently be compressed into atablet.

As an alternative to dry granulation, a blended composition may becompressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well suitedfor direct compression tableting include microcrystalline cellulose,spray dried lactose, dicalcium phosphate dihydrate and colloidal silica.The proper use of these and other excipients in direct compressiontableting is known to those in the art with experience and skill inparticular formulation challenges of direct compression tableting.

A capsule filling of the present invention may comprise any of theaforementioned blends and granulates that were described with referenceto tableting, however, they are not subjected to a final tableting step.

In another embodiment, the present invention provides a method oftreating a patient comprising administering to a patient in need thereofa therapeutically effective amount of the above substantially pureO-desmethylvenlafaxine. Preferably, the method is treating a patientsuffering from a condition which may be treated with a norepinephrine ora serotonin re-uptake inhibitor. Such patient may be suffering fromdepression.

Having described the invention with reference to certain preferredembodiments, other embodiments will become apparent to one skilled inthe art from consideration of the specification. The invention isfurther defined by reference to the following examples describing indetail the synthesis of the novel compound tridesmethyl venlafaxine andfurther its conversion to O-desmethylvenlafaxine. It will be apparent tothose skilled in the art that many modifications, both to materials andmethods, may be practiced without departing from the scope of theinvention.

EXAMPLES

The XRD diffraction was performed on Scintag X-ray powder diffractometermodel X'TRA with a solid state detector. Copper radiation of 1.5418 Åwas used. The sample holder was a round standard aluminum sample holderwith rough zero background. The scanning parameters were range: 2-40degrees two-theta; scan mode: continuous scan; step size: 0.05 deg.; andat a rate of 5 deg/min.

HPLC Method for Measuring the Chemical Purity: Column Zorbax SB C-184.6*250 mm Part No. 28105-020 or equivalent column Buffer 0.4%trifluoroacetic acid, 0.7% triethylamine 98.9% of water (adjusted to pH= 3.0). Eluent A: 30% Acetonitrile 70% Buffer Eluent B: Prepared byadding to a mixture of 700 ml Acetonitrile and 300 ml buffer, 1.6 ml oftrifluoroacetic acid and 2.9 ml of triethylamine (adjusted to pH = 3.0)Stop time: 55 min Gradient of Eluent: Time (min) Eluent A (%) Eluent B(%) 0 100 0 21 100 0 55 45 55 Equilibration time: 10 min Flow: 1.0mL/min Detector: 230 nm Injection volume: 10 μL Diluent: Eluent A Columntemperature: 25° C.

Example 1 Preparation of O-Desmethylvenlafaxine in NMP

Venlafaxine (50 g, 180 mmol), thiophenol (20 ml, 195 mmol), K₂CO₃ (1 g,6 mmol), and NMP (90 ml) were charged in a 500 ml 3 necks flask equippedwith stirrer, condenser and thermometer. The mixture was heated to 190°C. After 5 hours at 190° C. the heating bath was removed. (less than1.5% VNL). At 80° C. IPA (300 ml) was added. The solution was cooled to0-5° C. overnight. The solid was filtered under reduced pressure andwashed with IPA and water. The solid was then dried overnight at 50° C.under vacuum to get pure ODV base. ODV was obtained with a purity of 97%and an Assay of 93.5%.

Example 2 Preparation of O-Desmethylvenlafaxine in NMP

To one neck flask equipped with magnetic stirrer, dean stark, condenserand thermometer were added at room temperature under flow of nitrogenVNL (5 g, 18.2 mmol), Na₂S Hydrate (1.58 g, 12 mmol, assay >60%) and NMP(12 ml). The reaction mixture was heated to 150° C. in 1 hour and keptat this temperature for 7.5 hours. Then the reaction mixture was cooledto room temperature and stirred overnight at this temperature.Afterwards Na₂S hydrate (0.71 g, 5.4 mmol, assay >60%) was added. Themixture was heated to 165° C. in 1 hour and kept at this temperature for5 hours. After this time the reaction was cooled to 40° C., EPA (30 ml)and a 10% aqueous solution of citric acid (20 ml) were added slowlythrough a dropping funnel until light precipitation was observed (pH10). The suspension was stirred over weekend at room temperature and thesolid was filtered under reduced pressure and washed with IPA (20 ml).The solid was dried overnight in a vacuum oven at 50° C. to obtain dryODV (assay 55.2%, HPLC purity 99.11%)

Example 3 Preparation of O-Desmethylvenlafaxine Under Pressure

A 250 ml autoclave is charged with 5 g VNL (0.0182 mol), 3.81 g SodiumEthanethiolate (0.0458 mol, 2.5 eq) and NMP (10 ml). The reactionmixture is stirred from 30° C. to 220° C. and 1-20 bar pressure for 4 h.The mixture is then cooled to room temperature. At ambient temperatureIPA (10 ml) and water (10 ml) are added. To this mixture a 10% aqueoussolution of citric acid is added in order to reach pH about 12. A solidbegins to precipitate and is stirred at RT for 2.5 h. The solid is thenfiltered under reduced pressure and washed with solvent. The wet cake isdried in a vacuum oven at 50° C. to obtain pure ODV.

Example 4 Preparation of O-Desmethylvenlafaxine in DMA

To a 100 ml three necks flask equipped with mechanical stirrer,thermometer and condenser were added 5 g VNL (0.0182 mol), 3.81 g SodiumEthanethiolate (0.0458 mol, 2.5 eq) and Dimethylacetamide (10 ml). Themixture was heated to 135° C. for 4 h, and then it was cooled to roomtemperature. At ambient temperature IPA (10 ml) and water (10 ml) wereadded. The reaction mixture was clear. To this mixture (pH 13) a 10%aqueous solution of citric acid was added in order to reach pH 12.4. Asolid began to precipitate and was stirred at RT for 2.5 h. The solidwas then filtered under reduced pressure and washed with EPA. The wetcake was dried in a vacuum oven at 50° C. to obtain crude ODV (assay of78%, HPLC 99.84%).

Example 5 Preparation of O-Desmethylvenlafaxine in DMA

To a 100 ml three necks flask equipped with mechanical stirrer,thermometer and condenser were added 10 g VNL (0.0364 mol), 7.62 gSodium ethanethiolate (0.09 μmol, 2.5 eq) and dimethylacetamide (20 ml).The mixture was heated at 110° C. for 9 hours and then was cooled toroom temperature. At this temperature IPA (25 ml) and water (15 ml) wereadded. The reaction mixture was clear. To this mixture (pH 12.43) HCl32% was added to reach pH 10. A solid began to precipitate and wasstirred at ambient temperature for 2.5 hours. The solid was thenfiltered and washed with IPA. The wet cake was dried in a vacuum oven at50° C. to obtain ODV crude (assay of 77.9%, HPLC 94.98%).

Example 6 Preparation of O-Desmethylvenlafaxine in DMF

To a 100 ml three necks flask equipped with mechanical stirrer,thermometer and condenser were added 5 g VNL (0.0364 mol), 3.81 g Sodiumethanethiolate (0.0454 mol, 2.5 eq) and Dimethylformamide (10 ml). Themixture was heated to 135° C. for 3 hours and 20 minutes. The solutionwas then cooled to room temperature.

At this temperature ethylacetate (10 ml) was added and some materialprecipitated. The mixture was heated back to 70° C. and then cooledslowly to ambient temperature. The mixture was stirred overnight at thistemperature. Then to the mixture were added IPA, brine and citric acid10% to pH 9-10. The suspension was stirred at RT for five minutes andfiltered under reduced pressure. The wet cake was washed with IPA anddried in a vacuum oven overnight at 50° C. to obtain crude ODV (assay of76.3%, HPLC 99.29%).

Example 7 Preparation of O-desmethylvenlafaxine by Slurry in Water/IPA

1 g of ODV (GS 1652) was stirred for 2 h at ambient temperature in 5 mlof a mixture water:IPA (80:20). The slurry was stirred for 2 hours atambient temperature and the solid was filtered under reduced pressureand washed with 2 ml of water:IPA (80:20). The solid was dried in avacuum oven overnight at 50° C. to obtain dry pure ODV (assay of 98.7%,HPLC 99.93%)

Example 8 Preparation of O-Desmethylvenlafaxine by Slurry in Water

To a 100 ml flask equipped with magnetic stirrer were added at roomtemperature wet ODV (5.65 g) previously produced and water (40 ml). Thesuspension was stirred at ambient temperature for 2.5 hours. Thesuspension was then filtered under reduced pressure and washed withwater (10 ml). The solid was dried in a vacuum oven overnight at 50° C.to get a white pure solid ODV (assay 95%, HPLC purity 99%).

Example 9 Preparation of O-Desmethylvenlafaxine in NMP

To a three necks flask equipped with mechanical stirrer, condenser andthermometer were added at room temperature under flow of nitrogen VNL(12 g, 43.26 mmol), Na₂S Hydrate (6.2 g, 47.69 mmol, assay >60%) and NMP(24 ml). The reaction mixture was heated to 175° C. in 1 hour and keptat this temperature for 3 hours. Then the reaction mixture was cooled to90° C. Water (36 ml) and succinic acid (5 g, 42.34 mmol) were added anda light precipitation was observed (pH 8.0). Diethylcarbonate (24 ml)was added to the solution and the suspension was stirred at 60° C. 0.5hours. The reaction mixture was then cooled to room temperature and thesolid was filtered under reduced pressure and washed with H₂O (2×20 ml).The solid was dried overnight in a vacuum oven at 50° C. to obtain 9.26g (yield=79.43%) of dry pure ODV base (assay 97.7%, HPLC purity 99.34%)

Example 10 Preparation of O-Desmethylvenlafaxine in NMP

To a three necks flask equipped with mechanical stirrer, condenser andthermometer were added at room temperature under flow of nitrogen VNL(12 g, 43.26 mmol), Na₂S Hydrate (6.2 g, 47.69 mmol, assay >60%) and NMP(24 ml). The reaction mixture was heated to 175° C. in 1 hour and keptat this temperature for 3 hours. Then the reaction mixture was cooled to90° C. Water (36 ml) and succinic acid (6 g 50.8 mmol) were added and alight precipitation was observed (pH 8.0). Acetonitrile (24 ml) wasadded and the suspension was stirred at 60° C. for 0.5 hour. Then thereaction mixture was cooled to room temperature, the solid was filteredunder reduced pressure and washed with H₂O (2×20 ml). The solid wasdried overnight in a vacuum oven at 50° C. to obtain pure dry ODV base(assay 95.8%, HPLC purity 99.47%)

Example 11 Preparation of O-Desmethylvenlafaxine in NMP

To a three necks flask equipped with mechanical stirrer, condenser andthermometer were added at room temperature under flow of nitrogen VNL(12 g, 43.26 mmol), Na₂S Hydrate (6.2 g, 47.69 mmol, assay >60%) and NMP(24 ml). The reaction mixture was heated to 175° C. in 1.5 hour and keptat this temperature for 4 hours. Then the reaction mixture was cooled toroom temperature. Water (60 ml) and succinic acid (5 g 42.34 mmol) wereadded and precipitation was observed (pH 8.0). The suspension was heatedto 95° C. and stirred at 95° C. 1 hour. Then the reaction mixture wascooled to room temperature, the solid was filtered under reducedpressure and washed with H₂O (2×20 ml). The solid was dried overnight ina vacuum oven at 50° C. to obtain 11.34 g of ODV base (yield=95.38%,assay 95.8%, HPLC purity 98.07%).

Example 12 Preparation of Tridesmethyl Venlafaxine

DDMVxHCl (10 g, 40 mmol), K₂CO₃ (6 g, 44 mmol), Thiophenol (8 ml, 60mmol) and NMP (40 ml) were charged in a 250 ml flask equipped withmagnetic stirrer, condenser and nitrogen inlet, and heated in a sandbath. The temperature of the bath was kept at 210° C. for 5.5 hours.HPLC analysis confirmed full consumption of DDMV. TDMV was obtained witha purity of 95%.

Example 13 Preparation of Substantially Pure O-Desmethylvenlafaxine

TDMV (0.2 g, 0.85 mmol) was dissolved in methanol. Formalin solution(0.4 ml, 5 mmol) was added and the resulting solution was cooled in anice bath. To the cold solution, NaBH₄ (65 mg, 1.7 mmol) was added. After15 min a sample was analyzed by HPLC, and determined to contain 85% ODVin the reaction mixture.

Then to the mixture is added IPA, and citric acid 10% to pH 9-10. Thesuspension is stirred at RT for five minutes and filtered under reducedpressure. The wet cake is washed with IPA and dried in a vacuum ovenovernight at 50° C. to obtain pure ODV.

Comparative Example with WO 03/048104 Example 4

NaOMe (1.3 g, 24 mmol) dissolved in Methanol (3 ml) and dodecanethiol(5.83 ml=4.92 g, 24 mmol) were mixed together and placed in rotovaporunder reduced pressure at 90° C. To this residue Venlafaxine (5.12 g, 18mmol) and PEG 400 (3.7 g, 0.75 vol) were added. The mixture was thenheated at 200° C. (T_(internal)=190° C.). After 3 hours IPA (18 ml) wasadded and the pH adjusted to 9.5 with aqueous HCl. The solid wasfiltered under reduced pressure and washed with IPA and water. The wetODV was dried under reduced pressure to get ODV. ODV was obtained with apurity of 73.5% and an Assay of 74.2%

Comparative Example with WO 03/048104 Example 2

Venlafaxine (2.8 g, 10.1 mmol), Benzenethiolate sodium salt (3.45 g, 26mmol), and PEG 400 (12.5 g, 4.5 vol) were charged in a 100 ml flask withmagnetic stirrer. The mixture was heated in a sand bath to 160° C. At90° C. we observed a complete dissolution. After 5 hours at 160° C. thebath was removed and water (30 ml) was added. The pH was adjusted withH₃PO₄ 85% to pH=3.5. The mixture was extracted with 25 ml Hexane toremove organic by-products, and the aqueous phase pH was readjusted topH 9.5 with aqueous ammonia. A solid precipitated from the reactionmixture. The solid was filtered, reslurried in water (40 ml) andfiltered under reduced pressure. The solid so-obtained was dried underreduced pressure to get ODV. ODV was obtained with a purity of 95.6% andan Assay of 78.5%.

1. Substantially pure O-desmethylvenlafaxine, wherein the amount oftotal impurities is less than about 5% area by HPLC.
 2. (canceled) 3.The substantially pure O-desmethylvenlafaxine according to claim 1,wherein the amount of total impurities is less than about 3% area byHPLC.
 4. The substantially pure O-desmethylvenlafaxine according toclaim 3, wherein the amount of total impurities is less than about 1%area by HPLC.
 5. The substantially pure O-desmethylvenlafaxine accordingto claim 4, wherein the amount of total impurities is less than about0.7% area by HPLC.
 6. The substantially pure O-desmethylvenlafaxineaccording to claim 5, wherein the amount of total impurities is lessthan about 0.2% area by HPLC.
 7. The substantially pureO-desmethylvenlafaxine according to claim 6, wherein the amount of totalimpurities is less than about 0.07% area by HPLC.
 8. (canceled) 9.(canceled)
 10. (canceled)
 11. (canceled)
 12. (canceled)
 13. (canceled)14. (canceled)
 15. (canceled)
 16. (canceled)
 17. (canceled) 18.(canceled)
 19. (canceled)
 20. (canceled)
 21. (canceled)
 22. (canceled)23. (canceled)
 24. (canceled)
 25. (canceled)
 26. (canceled) 27.(canceled)
 28. (canceled)
 29. (canceled)
 30. (canceled) 31.-36.(canceled)
 37. A substantially pure O-desmethylvenlafaxine produced by aprocess of comprising the steps of; combining venlafaxine, an organicsolvent and a reagent selected from the group consisting of thiophenol,sodium sulfide, and a C₁-C₈ alkyl thiolate, to form a mixture; heatingthe mixture; and.
 38. The substantially pure O-desmethylvenlafaxineaccording to claim 37, having an assay purity of at least about 95%. 39.The substantially pure O-desmethylvenlafaxine according to claim 38,having an assay purity of at least about 99%.
 40. (canceled) 41.(canceled)
 42. (canceled) 43.-54. (canceled)
 55. A substantially pureO-desmethylvenlafaxine produced by a process comprising the steps of:combining venlafaxine and thiophenol to form a mixture; heating themixture to a temperature of about 100° C. to about 210° C.; andrecovering substantially pure O-desmethylvenlafaxine.
 56. Thesubstantially pure O-desmethylvenlafaxine according to claim 55, havingan assay purity of at least about 99%.
 57. (canceled)
 58. (canceled) 59.(canceled)
 60. (canceled)
 61. (canceled)
 62. (canceled)
 63. (canceled)64. (canceled)
 65. (canceled)
 66. (canceled)
 67. (canceled) 68.(canceled)
 69. (canceled)
 70. (canceled)
 71. (canceled)
 72. (canceled)73. A pharmaceutical composition comprising the substantially pureO-desmethylvenlafaxine of claim 1 and a pharmaceutically acceptableexcipient.
 74. A process for preparing a pharmaceutical formulationcomprising combining the substantially pure O-desmethylvenlafaxine ofclaim 1 and a pharmaceutically acceptable carrier.